The present invention is directed to purified diisocyanate polyetherurethane prepolymers, a process therefor, polyetherurethane urea polymers prepared by mixing said prepolymers with an aqueous solution of an amino, ureido, or hydroxy substituted amine or a like-substituted alpha-amino acid, and a method of using said polymers as a space filling adhesive in surgery.
Protection of the central nervous system (CNS) from aberrant peripheral influences partly stems from the physiological compartmentalization. The main function of the cranial meninges and the cerebrospinal fluid (CSF) is to provide support and protection for the brain, in addition to that afforded by the calvaria.
The brain, having approximately the same specific gravity as the CSF, floats in the fluid thus being cushioned against momentary contortions by external forces. The surgical treatment of the CNS diseases, correction of CNS malformations, the care and repair of traumatic lesions of CNS, and the surgical palliation of pain and abnormal motor movements all require a disruption of the CNS homeostasis. Elimination of the extracranial communication resulting from neurologic surgery is required to preserve or restore the maximal degree of neurologic function possible with the disease state. The watertight closure of the dural incisions (especially when the dura contracts) and dural defects is accomplished with mixed success by suturing the dura with silk, sometimes with fascia or pericranium grafts. When the normal CSF pathway is violated and there is continuity between subarachnoid space and the skin and mucous membranes, there is an inherent risk of retrograde infection of the CNS system. Unsuccessful dural closure leads to CSF leaks and menningitis, side effects that are the bane of the surgical therapy of CNS disease. Several neurosurgical and otorhinolaryngological procedures are often accompanied by severe and sometimes fatal complications resulting from CSF rhinorrhea and/or otorrhea. Thus in the surgical therapy of CNS disease as well as in the otorhinolaryngological surgery of the head and neck there is a need for a permanent, space filling adhesive sealant to close dura in a watertight fashion, and to fill sinuses and cranial bone defects. The adhesive should be applicable as a viscous liquid which can be sculpted. Once hardened in place, it should be somewhat rubbery, not brittle and subject to shattering. It should comprise relatively high molecular weight molecules which cannot diffuse away from the site of application. Final polymerization in place should occur in the range of room temperature and physiological temperature with minimal or no generation of heat, and without significant shrinkage. Finally, the adhesive should be reproducibly prepared and non-toxic.
Luting agents, for filling cavities or spaces in human or other animal bones, comprising the reaction product of a polyetherurethane diisocyanate prepolymer, a curing agent and a filler, have been disclosed by Oechsle, U.S. Pat. No. 4,477,604. Exemplary of his prepolymers, which are not purified, is one derived by reacting "tolylene diisocyanate" (presumably toluene 2,4-diisocyanate) with polytetramethyleneglycol in 1.7 to 1 molar ratio at elevated temperature, conditions conducive to side reactions (e.g., branching and cross-linking). The key to that earlier invention lies in the mixing of equal volumes of the prepolymer and a preformed mixture of a filler (50-75%) and a curing agent (25-50%). Exemplary is a mixture composed of 50% of the same polytetramethyleneglycol used in the prepolymer, 30% butane (1,4?)-diol and 20% methylene bis dipropylaniline, a toxic substance. The prepolymer is crude and the interaction is therefore complicated by the fact that the prepolymer still contains the original excess of the toluene diisocyanate. The latter substances, as well as lower molecular weight amines derived therefrom, are toxic. In any event, based on isocyanate numbers, it is evident that the large volume of reactive curing agents and less reactive filler will provide a large molar excess of the toxic curing agent. In marked contrast, the space filling adhesive polymer of the present invention contains no filler, no excess of toxic chain extenders, and no toxic, lower molecular weight diisocyanates or derived diamines. It is formed from molar equivalents of a purified diisocyanate prepolymer, which is highly homogeneous in structure, and a generally much lower volume of an aqueous solution of the chain extender (curing agent). Thus incorporation of the chain extender compound into the polymer is substantially complete. In the most preferred embodiment of the present invention, a non-toxic, natural L-aminoacid is employed as chain extender.
British Patent No. 930,458 (1961) describes extractive methods for removing mixed toluene 2,4- and 2,6-diisocyanates from highly branched and cross-linked, structurally heterogeneous urethane polyisocyanates and isocyanurates. Davis et al., U.S. Pat. No. 3,415,790 describes the removal of phenyl-1,4-diisocyanate from structurally heterogeneous prepolymers (obtained by heating co-polyether glycols with said phenyl diisocyanate at 97.degree. ), with varying degrees of success, by extraction with propylene carbonate, acetonitrile or cyclohexane. The resulting prepolymers were in turn reacted with water and/or a diamine and wet spun into thread.
Rabizzoni, U.S. Pat. No. 3,883,577 prepared a highly branched and cross-linked, structurally heterogeneous prepolymer from mixed toluene diisocyanates and trimethylolpropane in acetonitrile at less than 40.degree. C., then heating at 60.degree. C. until the NCO number dropped to the desired level. The unreacted toluene diisocyanate was incompletely removed from the acetonitrile solution of prepolymer by a countercurrent type extraction with heptane. Acetonitrile was in turn removed by heating at 90.degree. C., ultimately in vacuum, to produce a product containing 0.3% toluene diisocyanates.
Alternatively, according to U.S. Pat. No. 4,385,171 unreacted toluene diisocyanates were removed from highly branched and cross-linked, structurally heterogeneous polymers derived by heating said toluene diisocyanates and polyether polyols by a codistillation method at 100.degree. C. The assay for residual toluene diisocyanates employed a petroleum ether extraction process. In another alternative method, Marams et al., U.S. Pat. No. 4,169,175 reduced toluene diisocyanates in similar such polymers from 2-3% to 1.0.+-.0.2 by selective absorption of the toluene diisocyanates on a zeolite (type X molecular sieve) column.